China has updated the drug registration rules and administrative measures for drug products regulated by the National Medical Products Administration ("NMPA"). On 1 July 2020, the new "Drug Registration Rules" ("DRR") (SAMR Order No.27) and new "Administrative Measures for Monitoring Drug Production" ("AMMDP") (SAMR Order No.28) came into force (the State Administration for Market Regulation (“SAMR”) had published the DRR and AMMDP on 30 March 2020). The DRR and AMMDP complement the new "Drug Administration Law" ("DAL") and the “Implementing Regulations of the Drug Administration Law” which entered into force in December 2019 and March 2019 respectively.
In this first part of a two part series, we will concentrate on the areas of market authorisation, the review and approval processes, liability, and alignment with the previous DRR. In the second part, to be published next week, we will consider some important elements of the DRR relating to the expedited approval pathways and the removal of certain IP and regulatory sections.
Full Implementation of the Market Authorisation Holder ("MAH") System
While already outlined in the DAL, the DRR clarifies that the MAH must be a company, or a drug R&D institution, with the capability to manage all of the responsibilities associated with a marketed drug product. Basically, the MAH is responsible for the quality, safety and efficacy of the product through its whole life cycle. This responsibility links to the requirements in the AMMDP that requires the MAH to have a quality assurance system and be able to manage all of the post marketing requirements.
The MAH is required to obtain a drug manufacture license, regardless of whether it has production capability. This requirement appears directed toward ensuring the MAH has the qualified personnel and policies to maintain drug quality even if it entrusts its manufacturing to other third parties. The drug manufacture license is also an important requirement for the MAH, as they will require this to be qualified for public procurement contracts and to issue proper invoices for such contracts.
Optimising Review and Approval Processes
The new DRR provides the specific elements for the review and approval procedure outlined in the DAL. Under the new DRR, product review, verification and site inspection occur can occur "in parallel" rather than "in series" as per the previous process. On the review and approval side, the new DRR reinforces the commitment to streamline and optimise government services related to drug review and approval through risk management principles. One simple clarification is that a reference to a number of days means "working days".
In terms of inspection, the new DRR onsite inspection is no longer mandatory for all drug varieties. The Center for Drug Evaluation (“CDE”) can determine whether an onsite inspection will be required through the consideration of a number of factors, e.g. drug variety, manufacturing process, manufacturing facilities, previous inspection results, etc. However, innovative new drugs, improved new drugs, and biological products shall still be subject to the on-site inspection requirements.
The commitment to whole lifecycle management of the drug product is evident with a focus on enhanced supervision of clinical and non-clinical drug research institutions. There will also be more attention paid to manufacturing through the implementation of quality management requirements for drug production and ongoing inspections. The CDE will also be required to publish their review decisions and the grounds for the decisions.
The new AMMDP mirrors Article 148 of the DAL in including liability for the government drug officers if they conceal, misstate, defer or under-report any drug safety incidents. This confirms the commitment to improve the response to quality incidents associated with drug products in China.
Aligning the New DRR with Previous DRR Requirements
As a result of enacting the new DRR, the NMPA issued a Notice on "Implementation of Drug Registration Regulations (2020, No.46)" on 30 March 2020, which outlines how to align the new DRR with the previous DRR rules it will replace for reviews etc already in process.
There are several changes on the application procedure. The new DRR will require the MA applicant to obtain a manufacturer's licence prior to submitting the MA application. This compares to the existing process of receiving the license after MA submission but before approval (MA applications accepted before the new DRR will continue with the existing system). In addition, any MA applications currently in place will continue under the existing system, unless the applicant wishes to withdraw the application and file again under the new process. Once approved, the term 'drug certificate' will be replaced by the term 'drug registration certificate'.
For the priority review procedures, any applications received under the existing process will continue to be assessed on that pathway. For drugs approved under the new DRR conditional approval process, they must meet the new DRR requirements (depending on the conditional approval path) and the new DAL requirements (e.g. Article 78 that requires risk management and completion of the clinical trial associated with the conditional approval).
There are also some amendments to the clinical trial procedures. The new DRR further clarifies the requirement that a clinical trial needs to commence within three years from the date of approval. The additional information in the new DRR is that if no subject signs the informed consent within 3 years from the date of approval, the clinical trial approval will expire.
Overall, the new DRR and AMMDP provide further clarity to the provisions of the new DAL. The obvious step toward improving the review and approval process, and the reduction in the need for onsite review for many products, will hopefully manifest as reduced approval times. The increased focus on the whole of life cycle management and more control over product manufacturing are also clear improvements to the regulatory requirements. We will discuss expedited review pathways and the removal of IP provisions in Part 2 of this series.